tbuckley/cabot-search huggingface dataset:
Down-regulation of Risa improves podocyte injury by enhancing autophagy in diabetic nephropathy
Authors: Pei-Pei Su, Dong-Wei Liu, Si-Jie Zhou, Hang Chen, Xian-Ming Wu, Zhang-Suo Liu
Journal: Military Medical Research (2022)

Abstract Background LncRNA AK044604 (regulator of insulin sensitivity and autophagy, Risa ) and autophagy-related factors Sirt1 and GSK3β play important roles in diabetic nephropathy (DN). In this study, we sought to explore the effect of Risa on Sirt1/GSK3β-induced podocyte injury. Methods Diabetic db/db mice received Risa -inhibition adeno-associated virus (AAV) via tail vein injection, and intraperitoneal injection of lithium chloride (LiCl). Blood, urine, and kidney tissue samples were collected and analyzed at different time points. Immortalized mouse podocyte cells (MPCs) were cultured and treated with Risa -inhibition lentivirus (LV), EX-527, and LiCl. MPCs were collected under different stimulations as noted. The effects of Risa on podocyte autophagy were examined by qRT-PCR, Western blotting analysis, transmission electron microscopy, Periodic Acid-Schiff staining, and immunofluorescence staining. Results Risa and activated GSK3β were overexpressed, but Sirt1 was downregulated in DN mice and high glucose-treated MPCs ( P &lt; 0.001, db/m vs. db/db, NG or HM vs. HG), which was correlated with poor prognosis. Risa overexpression attenuated Sirt1-mediated downstream autophagy levels and aggravated podocyte injury by inhibiting the expression of Sirt1 ( P &lt; 0.001, db/m vs. db/db, NG or HM vs. HG). In contrast, Risa suppression enhanced Sirt1-induced autophagy and attenuated podocyte injury, which could be abrogated by EX-527 ( P &lt; 0.001, db/db + Risa -AAV vs. db/db, HG + Risa -LV vs. HG). Furthermore, LiCl treatment could restore GSK3β-mediated autophagy of podocytes ( P &lt; 0.001, db/db + LiCl vs. db/db, HG + LiCl vs. HG), suggesting that Risa overexpression aggravated podocyte injury by decreasing autophagy. Conclusion Risa could inhibit autophagy by regulating the Sirt1/GSK3β axis, thereby aggravating podocyte injury in DN. Risa may serve as a therapeutic target for the treatment of DN.
Performance of plasma phosphorylated tau 181 and 217 in the community
Authors: Michelle M. Mielke, Jeffrey L. Dage, Ryan D. Frank, Alicia Algeciras-Schimnich, David S. Knopman, Val J. Lowe, Guojun Bu, Prashanthi Vemuri, Jonathan Graff-Radford, Clifford R. Jack, Ronald C. Petersen
Journal: Nature Medicine (2022)
The IGF2BP family of RNA binding proteins links epitranscriptomics to cancer
Authors: Deepthi Ramesh-Kumar, Sonia Guil
Journal: Seminars in Cancer Biology (2022)

RNA binding proteins that act at the post-transcriptional level display a richness of mechanisms to modulate the transcriptional output and respond to changing cellular conditions. The family of IGF2BP proteins recognize mRNAs modified by methylation and lengthen their lifecycle in the context of stable ribonucleoprotein particles to promote cancer progression. They are emerging as key 'reader' proteins in the epitranscriptomic field, driving the fate of bound substrates under physiological and disease conditions. Recent developments in the field include the recognition that noncoding substrates play crucial roles in mediating the pro-growth features of IGF2BP family, not only as regulated targets, but also as modulators of IGF2BP function themselves. In this review, we summarize the regulatory roles of IGF2BP proteins and link their molecular role as m6A modification readers to the cellular phenotype, thus providing a comprehensive insight into IGF2BP function.
Dynamic DNA 5-Hydroxylmethylcytosine and RNA 5-Methycytosine Reprogramming During Early Human Development
Authors: Xiao Han, Jia Guo, Mengke Wang, Nan Zhang, Jie Ren, Ying Yang, Xu Chi, Yusheng Chen, Huan Yao, Yong-Liang Zhao, Yun-Gui Yang, Yingpu Sun, Jiawei Xu
Journal: Genomics Proteomics & Bioinformatics (2022)
Automated 3D reconstruction of the fetal thorax in the standard atlas space from motion-corrupted MRI stacks for 21–36 weeks GA range
Authors: Alena U. Uus, Irina Grigorescu, Milou P.M. van Poppel, Johannes K. Steinweg, Thomas A. Roberts, Mary A. Rutherford, Joseph V. Hajnal, David F.A. Lloyd, Kuberan Pushparajah, Maria Deprez
Journal: Medical Image Analysis (2022)
Association of Bullous Pemphigoid With Immune Checkpoint Inhibitor Therapy in Patients With Cancer
Authors: Maria S. Asdourian, Nishi Shah, Ted V. Jacoby, Kerry L. Reynolds, Steven T. Chen
Journal: JAMA Dermatology (2022)

<h3>Importance</h3> There is limited information on immune checkpoint inhibitor–induced bullous pemphigoid (ICI-BP) in patients with cancer, with most existing studies being case reports or small case series from a single institution. Prior review attempts have not approached the literature in a systematic manner and have focused only on ICI-BP secondary to anti–programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) therapy. The current knowledge base of all aspects of ICI-BP is limited. <h3>Objective</h3> To characterize the risk factors, clinical presentation, diagnostic findings, treatments, and outcomes of ICI-BP in patients with cancer as reported in the current literature. <h3>Evidence Review</h3> A systematic review was performed using PubMed<i>,</i>Embase<i>,</i>Web of Science<i>,</i>and the Cochrane Database of Systematic Reviews according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Articles reporting data on individual patients who met preestablished inclusion criteria were selected, and a predefined set of data was abstracted. When possible, study results were quantitatively combined. <h3>Findings</h3> In total, 70 studies reporting data on 127 individual patients undergoing ICI therapy for cancer (median [IQR] age, 71 [64-77] years; 27 women [21.3%]) were included. In pooled analyses, patients ranged in age from 35 to 90 years. Immune checkpoint inhibitor–induced bullous pemphigoid often occurred during the course of anti-PD-1, PD-L1, or cytotoxic T lymphocyte–associated antigen 4 therapy but was also found to develop up to several months after treatment cessation. Prodromal symptoms, such as pruritus or nonspecific skin eruptions, were found in approximately half of the patient population. Histopathologic or serologic testing, when undertaken, was a helpful adjunct in establishing diagnosis. Treatment with immunotherapy was discontinued after ICI-BP development in most patients. The most common treatments were systemic and topical corticosteroids. Steroid-sparing therapies, such as antibiotics and other systemic immunomodulators, were also used as adjuvant treatment modalities. Biologic and targeted agents, used predominantly in cases refractory to treatment with corticosteroids, were associated with marked symptomatic improvement in most patients. <h3>Conclusions and Relevance</h3> The results of this systematic review suggest that ICI-BP often poses a therapeutic challenge for patients with cancer who are receiving immunotherapy. Further research on the early recognition, diagnosis, and use of targeted treatment modalities will be essential in developing more personalized treatment options for affected patients while minimizing morbidity and mortality.
Redefining breast cancer subtypes to guide treatment prioritization and maximize response: Predictive biomarkers across 10 cancer therapies
Authors: Denise M. Wolf, Christina Yau, Julia Wulfkuhle, Lamorna Brown-Swigart, Rosa I. Gallagher, Pei Rong Evelyn Lee, Zelos Zhu, Mark J. Magbanua, Rosalyn Sayaman, Nicholas O’Grady, Amrita Basu, Amy Delson, Jean Philippe Coppé, Ruixiao Lu, Jerome Braun, Smita M. Asare, Laura Sit, Jeffrey B. Matthews, Jane Perlmutter, Nola Hylton, Minetta C. Liu, Paula Pohlmann, W. Fraser Symmans, Hope S. Rugo, Claudine Isaacs, Angela M. DeMichele, Douglas Yee, Donald A. Berry, Lajos Pusztai, Emanuel F. Petricoin, Gillian L. Hirst, Laura J. Esserman, Laura J. van 't Veer
Journal: Cancer Cell (2022)

Using pre-treatment gene expression, protein/phosphoprotein, and clinical data from the I-SPY2 neoadjuvant platform trial (NCT01042379), we create alternative breast cancer subtypes incorporating tumor biology beyond clinical hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status to better predict drug responses. We assess the predictive performance of mechanism-of-action biomarkers from ∼990 patients treated with 10 regimens targeting diverse biology. We explore >11 subtyping schemas and identify treatment-subtype pairs maximizing the pathologic complete response (pCR) rate over the population. The best performing schemas incorporate Immune, DNA repair, and HER2/Luminal phenotypes. Subsequent treatment allocation increases the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. pCR gains from reclassification and improved patient selection are highest in HR+ subsets (>15%). As new treatments are introduced, the subtyping schema determines the minimum response needed to show efficacy. This data platform provides an unprecedented resource and supports the usage of response-based subtypes to guide future treatment prioritization.
Bone histomorphometry for the diagnosis of renal osteodystrophy: a call for harmonization of reference ranges
Authors: Hanne Skou Jørgensen, Ana Carina Ferreira, Patrick D’Haese, Mathias Haarhaus, Marc Vervloet, Marie-Helene Lafage-Proust, Anibal Ferreira, Pieter Evenepoel, Pieter Evenepoel, Patrick D'Haese, Anibal Ferreira, Goce Spasovski, Jorge Cannata-Andia, Justine Bacchetta, Marc Vervloet, Marie-Helene Lafage-Proust, Mathias Haarhaus, Sandro Mazzaferro, Syazrah Salam
Journal: Kidney International (2022)
Breast cancer chemotherapy induces vascular dysfunction and hypertension through a NOX4-dependent mechanism
Authors: Piotr Szczepaniak, Mateusz Siedlinski, Diana Hodorowicz-Zaniewska, Ryszard Nosalski, Tomasz P. Mikolajczyk, Aneta M. Dobosz, Anna Dikalova, Sergey Dikalov, Joanna Streb, Katarzyna Gara, Pawel Basta, Jaroslaw Krolczyk, Joanna Sulicka-Grodzicka, Ewelina Jozefczuk, Anna Dziewulska, Blessy Saju, Iwona Laksa, Wei Chen, John Dormer, Maciej Tomaszewski, Pasquale Maffia, Marta Czesnikiewicz-Guzik, Filippo Crea, Agnieszka Dobrzyn, Javid Moslehi, Tomasz Grodzicki, David G. Harrison, Tomasz J. Guzik
Journal: Journal of Clinical Investigation (2022)

Cardiovascular disease is the major cause of morbidity and mortality in breast cancer survivors. Chemotherapy contributes to this risk. We aimed to define the mechanisms of long-term vascular dysfunction caused by neoadjuvant chemotherapy (NACT) and identify novel therapeutic targets. We studied arteries from postmenopausal women who had undergone breast cancer treatment using docetaxel, doxorubicin, and cyclophosphamide (NACT) and from women with no history of such treatment matched for key clinical parameters. We explored mechanisms in WT and Nox4–/– mice and in human microvascular endothelial cells. Endothelium-dependent, NO-mediated vasodilatation was severely impaired in patients after NACT, while endothelium-independent responses remained normal. This was mimicked by a 24-hour exposure of arteries to NACT agents ex vivo. When applied individually, only docetaxel impaired endothelial function in human vessels. Mechanistic studies showed that NACT increased inhibitory eNOS phosphorylation of threonine 495 in a Rho-associated protein kinase–dependent (ROCK-dependent) manner and augmented vascular superoxide and hydrogen peroxide production and NADPH oxidase activity. Docetaxel increased expression of the NADPH oxidase NOX4 in endothelial and smooth muscle cells and NOX2 in the endothelium. A NOX4 increase in human arteries may be mediated epigenetically by diminished DNA methylation of the NOX4 promoter. Docetaxel induced endothelial dysfunction and hypertension in mice, and these were prevented in Nox4–/– mice and by pharmacological inhibition of Nox4 or Rock. Commonly used chemotherapeutic agents and, in particular, docetaxel alter vascular function by promoting the inhibitory phosphorylation of eNOS and enhancing ROS production by NADPH oxidases.
Use Patterns, Flavors, Brands, and Ingredients of Nonnicotine e-Cigarettes Among Adolescents, Young Adults, and Adults in the United States
Authors: Shivani Mathur Gaiha, Crystal Lin, Lauren Kass Lempert, Bonnie Halpern-Felsher
Journal: JAMA Network Open (2022)

Nonnicotine e-cigarettes contain chemicals, flavorants, and solvents that have known health harms and/or have not been proven safe for inhalation.To evaluate nonnicotine e-cigarette use patterns, including common flavors, brands, and ingredients.This cross-sectional study included a convenience sample of US residents aged 13 to 40 years who completed an online survey in November and December 2021. Quota sampling was used for an equal proportion of participants aged 13 to 17 years, 18 to 20 years, and 21 to 40 years, balanced for sex, race, and ethnicity per the latest US Census.Nonnicotine e-cigarette use (ever, past 30- and past 7-day, number of times used, time taken to finish); co-use with nicotine e-cigarettes; age at first try; and flavors, brands, and ingredients used.Overall, 6131 participants (mean [SD] age, 21.9 [6.8] years; range, 13-40 years; 3454 [56.3%] identifying as female) completed the survey (55.1% completion rate). Among all participants, 1590 (25.9%) had ever used a nonnicotine e-cigarette, 1021 (16.7%) used one in the past 30 days, and 760 (12.4%) used one in the past 7 days. By age group, 227 of 1630 participants aged 13 to 17 years (13.9%), 497 of 2033 participants aged 18 to 20 years (24.4%), 399 of 1041 participants aged 21 to 24 years (38.3%), and 467 of 1427 participants aged 25 to 40 years (32.7%) had ever used nonnicotine e-cigarettes. Among 1590 participants who had ever used a nonnicotine e-cigarette, 549 (34.5%) had used one more than 10 times; 1017 (63.9%) finished 1 nonnicotine e-cigarette in less than 1 week. Co-use of nonnicotine with nicotine e-cigarettes was reported by 1155 participants (18.8%), 1363 (22.2%) exclusively used nicotine e-cigarettes, and 431 (7.0%) exclusively used nonnicotine e-cigarettes. Most-used flavors were sweet, dessert, or candy (578 [36.3%]); fruit (532 [33.4%]); and mint or menthol (321 [20.2%]); similar flavor patterns were observed for the top 2 flavors among those who used nonnicotine e-cigarettes in the past 30 days, followed by combinations of coffee, alcohol, flower, plant, and mint or menthol flavors by age group. Participants most reported using tetrahydrocannabinol (587 [36.9%]), cannabidiol (537 [33.7%]), melatonin (438 [27.5%]), caffeine (428 [26.9%]), and essential oils (364 [22.9%]) in their nonnicotine e-cigarettes.In this study of adolescents, young adults, and adults, a sizeable proportion reported having used nonnicotine e-cigarettes and co-using them with nicotine e-cigarettes. Surveillance studies should further assess nonnicotine e-cigarette use patterns and regulations, and prevention should be developed to address youth appeal, unsubstantiated health claims, and possible health harms.
Ccl3 enhances docetaxel chemosensitivity in breast cancer by triggering proinflammatory macrophage polarization
Authors: Dandan Sheng, Wei Ma, Rui Zhang, Lei Zhou, Qiaodan Deng, Juchuanli Tu, Weilong Chen, Fuchuang Zhang, Nailong Gao, Mengxue Dong, Dong Wang, Fengkai Li, Yin Liu, Xueyan He, Shengzhong Duan, Lixing Zhang, Tong Liu, Suling Liu
Journal: Journal for ImmunoTherapy of Cancer (2022)

Although the antitumor efficacy of docetaxel (DTX) has long been attributed to the antimitotic activities, its impact on the tumor microenvironment (TME) has recently gained more attention. Macrophages are a major component of the TME and play a critical role in DTX efficacy; however, the underlying action mechanisms remain unclear.DTX chemotherapeutic efficacy was demonstrated via both macrophage depletion and C-C motif chemokine ligand 3 (Ccl3)-knockout transgenic allograft mouse model. Ccl3-knockdown and Ccl3-overexpressing breast cancer cell allografts were used for the in vivo study. Combination therapy was used to evaluate the effect of Ccl3 induction on DTX chemosensitivity. Vital regulatory molecules and pathways were identified using RNA sequencing. Macrophage phagocytosis of cancer cells and its influence on cancer cell proliferation under DTX treatment were assessed using an in vitro coculture assay. Serum and tumor samples from patients with breast cancer were used to demonstrate the clinical relevance of our study.Our study revealed that Ccl3 induced by DTX in macrophages and cancer cells was indispensable for the chemotherapeutic efficacy of DTX. DTX-induced Ccl3 promoted proinflammatory macrophage polarization and subsequently facilitated phagocytosis of breast cancer cells and cancer stem cells. Ccl3 overexpression in cancer cells promoted proinflammatory macrophage polarization to suppress tumor progression and increase DTX chemosensitivity. Mechanistically, DTX induced Ccl3 by relieving the inhibition of cAMP-response element binding protein on Ccl3 via reactive oxygen species accumulation, and Ccl3 then promoted proinflammatory macrophage polarization via activation of the Ccl3-C-C motif chemokine receptor 5-p38/interferon regulatory factor 5 pathway. High CCL3 expression predicted better prognosis, and high CCL3 induction revealed better DTX chemosensitivity in patients with breast cancer. Furthermore, both the Creb inhibitor and recombinant mouse Ccl3 significantly enhanced DTX chemosensitivity.Our results indicate that Ccl3 induced by DTX triggers proinflammatory macrophage polarization and subsequently facilitates phagocytosis of cancer cells. Ccl3 induction in combination with DTX may provide a promising therapeutic rationale for increasing DTX chemosensitivity in breast cancer.
Demethylation and Up-Regulation of an Oncogene after Hypomethylating Therapy
Authors: Yao-Chung Liu, Junsu Kwon, Emiliano Fabiani, Zhijian Xiao, Yanjing V. Liu, Matilde Y. Follo, Jinqin Liu, Huijun Huang, Chong Gao, Jun Liu, Giulia Falconi, Lia Valentini, Carmelo Gurnari, Carlo Finelli, Lucio Cocco, Jin-Hwang Liu, Adrianna I. Jones, Junyu Yang, Henry Yang, Julie A.I. Thoms, Ashwin Unnikrishnan, John E. Pimanda, Rongqing Pan, Mahmoud A. Bassal, Maria T. Voso, Daniel G. Tenen, Li Chai
Journal: New England Journal of Medicine (2022)

Although hypomethylating agents are currently used to treat patients with cancer, whether they can also reactivate and up-regulate oncogenes is not well elucidated.We examined the effect of hypomethylating agents on SALL4, a known oncogene that plays an important role in myelodysplastic syndrome and other cancers. Paired bone marrow samples that were obtained from two cohorts of patients with myelodysplastic syndrome before and after treatment with a hypomethylating agent were used to explore the relationships among changes in SALL4 expression, treatment response, and clinical outcome. Leukemic cell lines with low or undetectable SALL4 expression were used to study the relationship between SALL4 methylation and expression. A locus-specific demethylation technology, CRISPR-DNMT1-interacting RNA (CRISPR-DiR), was used to identify the CpG island that is critical for SALL4 expression.SALL4 up-regulation after treatment with hypomethylating agents was observed in 10 of 25 patients (40%) in cohort 1 and in 13 of 43 patients (30%) in cohort 2 and was associated with a worse outcome. Using CRISPR-DiR, we discovered that demethylation of a CpG island within the 5' untranslated region was critical for SALL4 expression. In cell lines and patients, we confirmed that treatment with a hypomethylating agent led to demethylation of the same CpG region and up-regulation of SALL4 expression.By combining analysis of patient samples with CRISPR-DiR technology, we found that demethylation and up-regulation of an oncogene after treatment with a hypomethylating agent can indeed occur and should be further studied. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).
The Promise of Single-cell Technology in Providing New Insights Into the Molecular Heterogeneity and Management of Acute Lymphoblastic Leukemia
Authors: Holly C.L. Pearson, Kooper V. Hunt, Toby N. Trahair, Richard B. Lock, Heather J. Lee, Charles E. de Bock
Journal: HemaSphere (2022)

Drug resistance and treatment failure in pediatric acute lymphoblastic leukemia (ALL) are in part driven by tumor heterogeneity and clonal evolution. Although bulk tumor genomic analyses have provided some insight into these processes, single-cell sequencing has emerged as a powerful technique to profile individual cells in unprecedented detail. Since the introduction of single-cell RNA sequencing, we now have the capability to capture not only transcriptomic, but also genomic, epigenetic, and proteomic variation between single cells separately and in combination. This rapidly evolving field has the potential to transform our understanding of the fundamental biology of pediatric ALL and guide the management of ALL patients to improve their clinical outcome. Here, we discuss the impact single-cell sequencing has had on our understanding of tumor heterogeneity and clonal evolution in ALL and provide examples of how single-cell technology can be integrated into the clinic to inform treatment decisions for children with high-risk disease.
Ebstein Anomaly—Of Veils and Visions
Authors: Elizabeth H. Stephens, Joseph A. Dearani
Journal: JAMA (2022)

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In this Issue
Authors: Ruth Williams
Journal: Circulation Research (2022)

Tenascin-X suppresses atherosclerosis in areas of unhindered blood flow, say Liang et al.Just as sediment in a river accumulates in areas of slow or disturbed water currents, so atherosclerotic plaques in arteries arise where blood flow is reduced or turbulent-such as where vessels curve or branch.Disturbed flow in these regions can prompt the local endothelial cells (ECs) to undergo endothelial-to-mesenchymal transition (EndMT), which in turn promotes plaque formation.Exactly why turbulent but not lamina flow (the steady movement of blood in one direction) prompts EndMT, however, is unclear.Using in vitro and in vivo experiments, Liang and colleagues have now discovered a critical EndMT-suppressor protein expressed at high levels in ECs exposed to lamina, but not turbulent, flow.Mice that lacked the protein, called tenascin-X (TN-X), exhibited signs of EndMT and inflammation throughout their aortas and were more prone to atherosclerosis, the team discovered.They also showed that TN-X bound and blocked the function of cytokine TGFβ-a potent driver of EndMT.Inhibiting the activity of TGFβ, whether with anti-TGFβ antibodies or by deletion of its receptors, prevented the EndMT-promoting effects of TN-X loss.Together, the results suggest that bolstering or mimicking the effects of TN-X may be a novel strategy for preventing atherosclerosis progression.